Mucosal Cellular Immunity in HIV Infection

This research project focuses on the cellular immune defense against mucosal HIV-1 infection (R37-NIAID). The acquisition of HIV-1 infection occurs most often by sexual transmission at mucosal epithelial surfaces, however the factors that control HIV-1 infectivity in the genital and rectal mucosa have not been described. The investigators have previously demonstrated the presence of HIV-1-specific MHC-restricted CD8+ and CD4+ CTL in the mucosa of HIV-1 individuals. These cells are capable of both destroying HIV-1 infected cells and releasing anti-viral cytokines. The overall goals of this study are to determine the role of T-cell immunity in the genitorectal mucosa in the clearance and control of HIV-1 infection and to examine the feasibility of inducing local immune responses by mucosal administration of HIV-1 vaccines.

The specific aims of this study are to:

1. Identify the viral and host factors that are associated with the induction and maintenance of mucosal CTL in HIV-1 infection. The kinetics of CTL induction are being determined in studies of patients with primary and clinically stable infection.
2. Determine if mucosal CTL can prevent HIV-1 dissemination in uninfected individuals who are persistently exposed to HIV-1 through sexual contact. This investigation involves uninfected male and female volunteers who report frequent high-risk sexual activity with a known HIV-1 positive partner. The investigators are testing semen, cervical and rectal mucosa for the presence and specificity of CD8+ and CD4+ CTL that can recognize autologous cells infected with the partner's virus, other prototype HIV-1 strains, and primary HIV-1 isolates.
3. Determine if mucosal administration of candidate HIV-1 vaccines can induce HIV-1 specific CTL in the genital tract and rectum. These studies are conducted through the UW AVEU using HIV-1 vaccine regimens that are known to induce systemic CTL after parenteral administration. The investigators are examining the ability of persistent vaccine-induced CTL to recognize targets infected with vaccine strains, mucosa-derived primary isolates, and clade-specific isolates.

Publications:

L. Musey, Y. Hu, L. Eckert, M. Christensen, T. Karchmer, and M.J. McElrath .   HIV-1 induces specific cytotoxic T lymphocytes in the cervix of infected women.   J Exp Med. 185:293-302, 1997.

F. Hladik, G. Lentz, R. Akridge, G. Peterson, H. Kelley, A. McElroy, and M.J. McElrath .   Dendritic cell/T cell interactions support co-receptor independent HIV-1 transmission in the human genital tract.   J Virology.   73:5833-5842, 1999.

F. Hladik, G. Lentz, A. McElroy, and M.J. McElrath .   Co-expression of CCR5 and IL-2 in human genital but not blood T cells:   implications for the ontogeny of the CCR5 +  TH1 phenotype.   J Immunol. 163:2306-2313, 1999.

L. Musey, Y. Ding, J. Cao, J. Lee, C. Galloway, A. Yuen, K.R. Jerome and M.J. McElrath.   Ontogeny and specificities of mucosal and blood HIV-1-specific CD8+ cytotoxic T lymphocytes.   J. Virology.   77:291-300, 2003.